A novel risk prediction tool for contrast-induced nephropathy in patients with chronic kidney disease who underwent diagnostic coronary angiography.

OBJECTIVE: The incidence of contrast-induced nephropathy (CIN) is higher than 20% in patients with chronic kidney disease. In this study, we sought to define the predictors of CIN and develop a risk prediction tool in patients with chronic kidney disease. PATIENTS AND METHODS: Patients aged 18 years and older who underwent invasive coronary angiography with an iodine-based contrast media between March 2014 and June 2017 were retrospectively analyzed. Independent predictors for CIN development were identified and a new risk prediction tool was created that included these predictors. RESULTS: In total, 283 patients included in the study were divided into those who developed CIN (n=39, 13.8%) and those who did not (n=244, 86.2%). Male gender (OR: 4.874, 95% CI: 2.044-11.621), LVEF (OR: 0.965, 95% CI: 0.936-0.995), diabetes mellitus (OR: 1.711, 95% CI: 1.094-2.677), and e-GFR (OR: 0.880, 95% CI: 0.845-0.917), were identified as independent predictors for the development of CIN in the multivariate analysis. A new scoring system has been designed that can score a minimum of 0 and a maximum of 8 points. Patients with a new scoring system score of ≥4 were at approximately 40 times higher risk of developing CIN than others (OR: 39.9, 95% CI: 5.4-295.3). The area under the curve value of CIN's new scoring system was 0.873 (95% CI, 0.821-0.925). CONCLUSIONS: We found that four easily accessible and routinely collected variables, including sex, diabetes status, e-GFR, and LVEF, were independently associated with the development of CIN. We believe that using this risk prediction tool in routine clinical practice may guide physicians to use preventive medications and techniques in high-risk patients for CIN.

Clinical utility of comprehensive circulating tumor DNA genotyping compared with standard of care tissue testing in patients with newly diagnosed metastatic colorectal cancer.

BACKGROUND: Comprehensive biomarker testing is essential in selecting optimal treatment for patients with metastatic colorectal cancer (mCRC); however, incomplete genotyping is widespread, with most patients not receiving testing for all guideline-recommended biomarkers, in part due to reliance on burdensome sequential tissue-based single-biomarker tests with long waiting times or availability of only archival tissue samples. We aimed to demonstrate that liquid biopsy, associated with rapid turnaround time (TAT) and lower patient burden, effectively identifies guideline-recommended biomarkers in mCRC relative to standard of care (SOC) tissue testing. PATIENTS AND METHODS: Prospectively enrolled patients with previously untreated mCRC undergoing physician discretion SOC tissue genotyping submitted pretreatment blood samples for comprehensive circulating tumor DNA (ctDNA) analysis with Guardant360 and targeted RAS and BRAF analysis with OncoBEAM. RESULTS: Among 155 patients, physician discretion SOC tissue genotyping identified a guideline-recommended biomarker in 82 patients, versus 88 identified with comprehensive ctDNA (52.9% versus 56.8%, noninferiority demonstrated down to α = 0.005) and 69 identified with targeted PCR ctDNA analysis (52.9% versus 44.5%, noninferiority rejected at α = 0.05). Utilizing ctDNA in addition to tissue increased patient identification for a guideline-recommended biomarker by 19.5% by rescuing those without tissue results either due to tissue insufficiency, test failure, or false negatives. ctDNA median TAT was significantly faster than tissue testing when the complete process from sample acquisition to results was considered (median 10 versus 27 days, P < 0.0001), resulting in accelerated biomarker discovery, with 52.0% biomarker-positive patients identified by ctDNA versus 10.2% by SOC tissue 10 days after sample collection (P < 0.0001). CONCLUSIONS: Comprehensive ctDNA genotyping accurately identifies guideline-recommended biomarkers in patients with mCRC at a rate at least as high as SOC tissue genotyping, in a much shorter time. Based on these findings, the addition of ctDNA genotyping to clinical practice has significant potential to improve the care of patients with mCRC.

Effect of Decorin and Bevacizumab on oxygen-induced retinopathy in rat models: A comparative study.

Purpose: The aims of this study were to evaluate the effects of decorin (DCN) in rat oxygen-induced retinopathy (OIR) model and to compare the results with those of bevacizumab. Methods: Twenty-eight newborn Sprague-Dawley rats were randomly divided into four groups. Group I (control): normoxia plus intraperitoneal (ip) normal saline (NS), Group II (sham): OIR plus ip NS, Group III (DCN): OIR plus ip 0.1 mg/kg DCN, and Group IV (bevacizumab): OIR plus ip 2.5 mg/kg bevacizumab. The OIR model was induced by cycling the oxygen concentration between 50% and 10% every 24 h for 14 days following their birth. In all groups, injections were administered on postnatal day (PD) 15. All animals were sacrificed and their right eyes were enucleated on PD 18. The nuclei of neovascular endothelial cells on the vitreal side of the inner limiting membrane were counted, and vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF)-α immunoreactivity were detected in histopathological and immunohistochemical examinations. One-way analysis of variance and post hoc Tukey tests were used for statistical analyses of the data. Results: In Groups II, III, and IV, the mean neovascular cell nuclei counts were 13.14 ± 1.34, 6.57 ± 1.51, and 6.71 ± 1.49, respectively. The mean neovascular cell nuclei count was significantly reduced in treatment groups compared with sham group (P < 0.001). In immunohistochemical staining, the immunoreactivity of VEGF was 0.07 ± 0.02, 0.97 ± 0.21, 0.37 ± 0.12, and 0.23 ± 0.17, respectively. Likewise, immunoreactivity of TNF-α was 0.02 ± 0.02, 1.11 ± 0.36, 0.37 ± 0.13, and 0.62 ± 0.21, respectively. VEGF and TNF-α immunoreactivity increased markedly in the sham group compared with those in the control group (P < 0.001). VEGF and TNF-α immunoreactivity of treatment groups decreased significantly compared to sham group (P < 0.001). Conclusion: The beneficial effects obtained by DCN administration in OIR model were comparable to the effects of bevacizumab.

Phase II study of high-sensitivity genotyping of KRAS, NRAS, BRAF and PIK3CA to ultra-select metastatic colorectal cancer patients for panitumumab plus FOLFIRI: the ULTRA trial.

BACKGROUND: Several studies show the importance of accurately quantifying not only KRAS and other low-abundant mutations because benefits of anti-EGFR therapies may depend on certain sensitivity thresholds. We assessed whether ultra-selection of patients using a high-sensitive digital PCR (dPCR) to determine KRAS, NRAS, BRAF and PIK3CA status can improve clinical outcomes of panitumumab plus FOLFIRI. PATIENTS AND METHODS: This was a single-arm phase II trial that analysed 38 KRAS, NRAS, BRAF and PIK3CA hotspots in tumour tissues of irinotecan-resistant metastatic colorectal cancer patients who received panitumumab plus FOLFIRI until disease progression or early withdrawal. Mutation profiles were identified by nanofluidic dPCR and correlated with clinical outcomes (ORR, overall response rate; PFS, progression-free survival; OS, overall survival) using cut-offs from 0% to 5%. A quantitative PCR (qPCR) analysis was also performed. RESULTS: Seventy-two evaluable patients were enrolled. RAS (KRAS/NRAS) mutations were detected in 23 (32%) patients and RAS/BRAF mutations in 25 (35%) by dPCR, while they were detected in 7 (10%) and 11 (15%) patients, respectively, by qPCR. PIK3CA mutations were not considered in the analyses as they were only detected in 2 (3%) patients by dPCR and in 1 (1%) patient by qPCR. The use of different dPCR cut-offs for RAS (KRAS/NRAS) and RAS/BRAF analyses translated into differential clinical outcomes. The highest ORR, PFS and OS in wild-type patients with their lowest values in patients with mutations were achieved with a 5% cut-off. We observed similar outcomes in RAS/BRAF wild-type and mutant patients defined by qPCR. CONCLUSIONS: High-sensitive dPCR accurately identified patients with KRAS, NRAS, BRAF and PIK3CA mutations. The optimal RAS/BRAF mutational cut-off for outcome prediction is 5%, which explains that the predictive performance of qPCR was not improved by dPCR. The biological and clinical implications of low-frequent mutated alleles warrant further investigations. CLINICALTRIALS.GOV NUMBER: NCT01704703. EUDRACT NUMBER: 2012-001955-38.

Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil or FOLFOX administration.

The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale.

The value of genetic polymorphisms to predict toxicity in metastatic colorectal patients with irinotecan-based regimens.

PURPOSE: We are trying to identify predictive factors of high risk of toxicity by analyzing candidate genes in the irinotecan pathways in order to identify useful tools to improve mCRC patient management under real practice conditions. METHODS: Genomic DNA was genotyped for UGT1A1 (*28, *60 and *93) from all 101 patients, and irinotecan dose was 180 mg/m(2) every second week. Clinical data were obtained by retrospective chart review. The primary endpoint is to find out whether the pharmacogenetic test in the clinical practice may predict toxicity. RESULTS: Grade 3/4 diarrhea occurred in twelve patients and required dose reduction in six patients, and neutropenia reached grade 3/4 in 19 patients (only one patient with *28/*28 genotype). The UGT1A1*93 seemed to relate with grade 3/4 neutropenia but only in the heterozygote state (G/A), p = 0.071, and UGT1A*60 showed no association with neutropenia. Twenty-eight percentage of patients required the use of G-CSF; 64.3% of them harbored *1/*28 or *28/*28 genotypes, p = 0.003. Thirty-seven (36.6%) patients required dose reduction of irinotecan and/or 5-FU owing to toxicity, mainly neutropenia and diarrhea. No significant association was detected between *28, *60 and *93 UGT1A variants and severe irinotecan-associated hematologic or GI toxicity. CONCLUSION: The impact of increased risk of toxicity attributed to the UGT1A variants may be offset by irinotecan in clinical practice by dose reduction or the use of colony-stimulating factor.

Comparative analysis of Met-enkephalin, galanin and GABA immunoreactivity in the developing trout preoptic-hypophyseal system.

We studied the organization of Met-enkephalin-containing cells and fibers in the developing preoptic-hypophyseal system of the brown trout (Salmo trutta fario) by immunohistochemistry and determined the relationship of these cells and fibers to the galaninergic and GABAergic systems. Met-enkephalin immunoreactivity was observed in cells in the preoptic area, the hypothalamus and the pituitary of late larvae. In the hypophysis, a few Met-enkephalin-containing cells were present in all divisions of the adenohypophysis, and some immunoreactive fibers were present in the interdigitations of the neural lobe with the proximal pars distalis. Concurrently, GABAergic fibers innervated the anterior and posterior neural lobe. Galanin cells coexisted with Met-enkephalin cells in neuronal groups of the preoptic-hypophyseal system. Galaninergic and GABAergic fibers innervated the preoptic and hypothalamic areas, but GABAergic fibers containing galanin were not observed. These results indicate that Met-enkephalin, galanin and GABA may modulate neuroendocrine activities in the preoptic area, hypothalamus and pituitary during the transition from larval to juvenile period. To better know how the development of the trout preoptic-hypophyseal system takes place, we studied the patterns of cell proliferation and expression of Pax6, a conserved transcription factor involved in the hypophysis development. Pax6 expressing cells and proliferating cells were present in the Rathke's pouch, the hypothalamus and the hypophysis of early larvae. In late larvae, Pax6 expression was no longer observed in these areas, and the density of proliferating cells largely decreased throughout development, although they remained in the hypophysis of late larvae and juveniles, suggesting that Pax6 might play an important role in the early regionalization of the pituitary in the trout.

Disnea súbita después del terremoto / After the earthquake sudden dyspnea

Fat embolism syndrome (FES) remains a diagnostic challenge for physicians. It is commonly as associated with fractures of long bones and it is a major source of morbidity and mortality inpatients with multiple injuries. Overall mortality is between 5-15 percent in all studies. These facts motivate us to present the case of a young woman suffering bone fractures in both legs during the earthquake in Chile on February 27, 2010. She presented a FES 72 hours later. It is important to understand this syndrome, as it can be confused with other serious diseases that require different management. We should be able to have a high FES suspicion in the appropriate context, in as much as an early diagnosis, and treatment may improve the prognosis of this severe condition.

El síndrome de embolia grasa (SEG) sigue siendo un reto diagnóstico para los médicos. Se asocia fundamentalmente en fracturas de los huesos largos y es una importante fuente de morbilidad y mortalidad en pacientes politraumatizados. La mortalidad general se encuentra entre el 5 a 15 por ciento en todos los estudios. Esto nos motiva a presentar el caso de una mujer joven que 72 horas después de fracturas sufridas durante el terremoto ocurrido en Chile el 27 de febrero del 2010, presentó un SEG. Es importante conocer este síndrome, ya que se puede confundir con otras patologías graves que requieren un manejo distinto y al tener una alta sospecha en el contexto adecuado, se permite un diagnóstico oportuno, tratamiento precoz y mejorar el pronóstico.

Radioquimioterapia neoadyuvante en cáncer gástrico T4 localmente irresecable: resultados preliminares / Chemoradiotherapy in patients with non resectable gastric cancer: report of 10 patients

En el caso de pacientes con cáncer gástrico T4, puede estar indicada la quimiorradioterapia si no es posible la resección de las estructuras infiltradas. Analizamos 10 pacientes con cáncer gástrico irresecable (8 hombres, 2 mujeres) tratados por nosotros en el periodo 2003-2005. Después de la laparotomía exploradora, los pacientes con cáncer gástrico localmente avanzados e irresecables son tratados con RT-QT concomitante 2 semanas después de la laparotomía. El tratamiento consistió en radioterapia a dosis de 45 Gy en 25 fracciones de 1.8 Gy, 5 veces por semana por 5 semanas sobre estómago y linfáticosregionales, y 5 FU en 1ª y 5º semana (425mg/m2) o Capecitabina 825 mg/m2 diarios, en dos dosis, cada12 hrs. Un mes después se realiza la segunda laparotomía con resección del estómago y linfadenectomía en casos de remisión total o parcial de la enfermedad. Todos los carcinomas fueron proximales. Nueve pacientes se reintervinieron, un paciente tuvo progresión de la enfermedad. Un paciente fue nuevamente irresecable y ocho fueron sometidos a una gastrectomía total D2. Se logró respuesta patológica completa en tres casos (no había cáncer residual en el estómago ni en los ganglios) y parcial en cinco. Creemos que en cáncer gástrico T4 localmente irresecable la RT-QT seguida de cirugía es una buena alternativa terapéutica.

Encontrar una familia en la calle / Finding a family in the streets

El presente estudio fue realizado por el Grupo de Investigación de Cultura y Salud, en la ciudad de Medellín, Colombia, con niños en situación de calle que participaron en la película "La vendedora de rosas".Objetivo: Evidenciar el significado que tiene para ellos el hogar y la familia. Metodología: Para la comprensión del fenómeno se partió del punto de vista de los participantes mediante el enfoque etnográfico y la perspectiva de la investigación cualitativa. Resultados: Muestran el significado que los niños dan a su hogar, al transito de este a la calle y de como encuentran la familia deseada y el regreso al hogar. Conclusiones: Las personas que viven en situación de calle salen de sus hogares por diversos motivos, como falta de afecto, maltrato y búsqueda de libertad y, al llegar allí, necesitan sobrevivir, acción que se facilita con la intervención de los mediadores, quienes les permiten encontrar la que consideran su verdadera familia. Al final del artículo se incluye un glosario con los términos utilizados por los niños de la calle.

Apendicectomía y apéndice normal: análisis de 107 exploraciones negativas / Appendicectomy and normal appendix: analysis of 107 negative explorations

Introducción: La clínica es fundamental para el diagnóstico de la apendicitis aguda aunque esto no siempre es fácil porque no hay síntomas, signos o exámenes complementarios que nos aseguren un diagnóstico correcto en todos los casos. Las variaciones en la posición del apéndice, edad del paciente, y grado de la inflamación hacen que la presentación clínica de la apendicitis sea muy diversa. La extirpación de un apéndice normal por sospecha de apendicitis es más frecuente en mujeres en edad fértil. La proporción de apéndices normales extirpados innecesariamente alta (15-30 por ciento)a pesar de varias técnicas e investigaciones utilizadas para mejorar la exactitud diagnóstica. La evaluación rápida o inexacta de los pacientes puede llevar a una laparotomía innecesaria que no está exenta de morbilidad. Material y Método: Se estudian 2617 pacientes que ingresaron con el diagnóstico de apendicitis aguda y que fueron operados en el Hospital Clínico Regional de Concepción en el período 1995-2000. En el 95,9 por ciento de los 2617 intervenidos se confirmó el diagnóstico preoperatorio con el análisis histopatológico de la pieza operatoria. 107 pacientes (4,1 por ciento) no tenían apendicular. El promedio de edad de este grupo fue de 33,9 años (rango: 15-83)y de los 107 pacientes72,9 por ciento corresponden al sexo femenino. Resultado: El síntoma más importante fue el dolor abdominal (97,2 por ciento). Este fue difuso en 10,3 por ciento de los casos y localizado en la fosa ilíaca derecha en el 76,6 por ciento de casos. Náuseas y vómitos se presentaron en 14 por ciento de los pacientes. En el examen físico se destaca el dolor localizado en fosa ilíaca derecha en 76 pacientes (71 por ciento), defensa muscular en 35 pacientes (32,7 por ciento) y dolor de rebote en el 66,4 por ciento. Sólo el 33,6 por ciento de los pacientes presentaba temperatura mayor a 37,5º C. Leucocitosis se observó en 49 pacientes (45,8 por ciento). Se presentaron complicaciones en 5 pacientes (4,7 por ciento). En 52 casos (48,5 por ciento) se demostró la presencia de patología de tipo ginecológica. La duración de la hospitalización postoperatoria fue de 3,5 días (el rango, 1 a 16 días). No hubo mortalidad en la serie. Conclusión: En el hospital Clínico Regional de Concepción la incidencia de apendicectomía con apéndice normal es baja y la mayor parte corresponden a pacientes con patología ginecológica.

Gastrectomía total en pacientes mayores de 65 años / Total gastrectomy in patients older than sixty five years

Introducción: En los últimos años se han producido un aumento de la población anciana que debe ser sometida a gastrectomía pos cáncer gástrico. Algunos autores consideran a la edad como un factor de riesgo importante de morbimortalidad en cirugía. Otros consideran que son las patología concomitantes y no la edad las que aumentan el riesgo. Material y Métodos: Estudio retrospectivos de los pacientes portadores de cáncer gástrico sometidos a gastrectomía total en el Hospital Clínico Regional de Concepción entre los años 1985 y 1999. Se dividen en grupo I, menores de 65 años. Resultados: Se estudian 263 pacientes, 162 menores de 65 años. La distribución por sexo fue similar (73,3 por ciento en grupo II). Los pacientes ancianos presentaron un 36,9 por ciento de patología concominate y los jóvenes un 14,8 por ciento (p< 0,000086). Las características de los tumores (localización, grado de diferenciación y profundidad de invasión) fueron similares en los grupos. En los ancianos predominó el tipo intestinal de Lauren (58,6 por ciento) y en los jóvenes el tipo difuso (56,1 por ciento) (p< 0,03). Los jóvenes fueron etapificados principalmente en el grupo III (67,3 por ciento), los ancianos se distribuyeron en las etapas II (22,8 por ciento), IIIA (28,7 por ciento) y IV (23,7 por ciento) (p<0,0005). La mortalidad fue de 24,1 por ciento en el grupo I y 37,6 por ciento en el grupo II (ns), y predominaron las complicaciones respiratorias. La mortalidad fue de 2,5 por ciento en el grupo I y 6,9 por ciento en el grupo II (ns). La estadía hospitalaria fue similar en ambos grupos. Conclusiones: Un 38,2 por ciento de los pacientes con cáncer gástrico sometidos a gastrectomía total son mayores de 65 años. Los ancianos presentan un mayor número de patologías asociadas que los jóvenes. Las características de los tumores son similares en ancianos y jóvenes. No existe relación entre la edad y la etapa del tumor. La morbilidad, mortalidad operatoria y estadía hospitalaria no mostraron diferencias significativas.

[Fear of progression in patients with cancer, diabetes mellitus and chronic arthritis]. / Progredienzangst bei Patienten mit Tumorerkrankungen, Diabetes mellitus und entzündlich-rheumatischen Erkrankungen.

Fear of an increasing disease progression (fear of progression) is among the main psychological stresses in patients with cancer, diabetes mellitus (type 1 and type 2) and chronic arthritis. The questions the study seeks to answer are: (1) Which are the main fears of these patients?, (2) How and in which circumstances in life do they occur?, (3) Which are the triggers of the fear? To answer these questions, a sample of 65 patients were researched through interviews. The results indicate that the predominant fears of cancer patients are the fear of dying and the unpredictability of the progression of the disease. Patients with chronic arthritis most frequently fear being physically dependent on someone else. The most common anxiety of diabetes patients are long-term complications. For all three groups of patients job-related fears cause a high amount of distress. These results contribute to the development of a standardised fear of progression questionnaire.

[Updating Fanconi's anaemia]. / Anemia de Fanconi. Consideraciones actuales.

Fanconi's anaemia (FA) is an autosomal recessive syndrome associated with chromosomal instability, and hypersensitivity of the DNA to claustrogenic agents. Clinically it presents a progressive marrow insufficiency, different congenital anomalies and an predisposition to malignancy. Eight complementation groups have been defined and the genes corresponding to six of them have been cloned. Recent advances in molecular biology have made it possible to investigate the relationship between the FA genotype and the nature and severity of the clinical phenotype. The treatment of FA is also the object of intense research that is currently centred on the transplant of hematopoyetic progenitors, especially successful in cases of an HLA-identical brother or sister donor, and in gene therapy, which is still in the phase of clinical research.

Motexafin gadolinium: a redox active drug that enhances the efficacy of bleomycin and doxorubicin.

The effect of motexafin gadolinium (MGd), a redox mediator, on tumor response to doxorubicin (Dox) and bleomycin (Bleo) was investigated in vitro and in vivo. MES-SA human uterine sarcoma cells were studied in vitro using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay. Rif-1, a murine fibrosarcoma cell line, was studied using a clonogenic survival assay. Tumor growth delay assays were performed using the EMT-6 murine mammary sarcoma cell line in BALB/c mice. MGd (25-100 microM) produced dose-dependent enhancement of Bleo cytotoxicity to MES-SA cells. The IC(50) for Bleo was reduced by approximately 10-fold using 100 microM MGd. In clonogenic assays using Rif-1 cells, MGd enhanced the activity of Bleo approximately 1000-fold. This effect was shown to be mediated, in part, by MGd inhibition of potentially lethal damage repair. MGd enhanced the tumor response to bleomycin and Dox in vivo. MGd had no significant effect on the systemic exposure to Dox (expressed in terms of the plasma area under the curve, 0-24 h) and did not increase Dox myelosuppression. MGd enhanced the effectiveness of the redox active drugs, Bleo and Dox.

MDR 1 activation is the predominant resistance mechanism selected by vinblastine in MES-SA cells.

Single-step selection with vinblastine was performed in populations of the human sarcoma cell line MES-SA, to assess cellular mechanisms of resistance to the drug and mutation rates via fluctuation analysis. At a stringent selection with 20 nM vinblastine, resulting in 5-6 logs of cell killing, the mutation rate was 7 x 10(-7)per cell generation. Analysis of variance supported the hypothesis of spontaneous mutations conferring vinblastine resistance, rather than induction of adaptive response elements. Surviving clones displayed a stable multidrug resistance phenotype over a 3-month period. All propagated clones demonstrated high levels of resistance to vinblastine and paclitaxel, and lower cross-resistance to doxorubicin and etoposide. Activation of MDR 1 gene expression and P-glycoprotein function was demonstrable in all clones. No elevation was found in the expression of the mrp gene, the LRP-56 major vault protein and beta-tubulin isotypes (M40, beta4, 5beta, and beta9) in these mutants. We conclude that initial-step resistant mechanism in these vinblastine-selected mutants commonly arises from a stochastic mutation event with activation of the MDR 1 gene.

Loss of cyclosporin and azidopine binding are associated with altered ATPase activity by a mutant P-glycoprotein with deleted phe(335).

In this study, we further characterize a mutant P-glycoprotein (P-gp) that has a deletion of Phe(335) and is resistant to inhibition by cyclosporins. Photoaffinity labeling with [(3)H]cyclosporine and [(3)H]azidopine revealed markedly decreased binding to the mutant P-gp compared with wild-type P-gp. Expression of the mutant P-gp in multidrug-resistant variant cell line MES-SA/DxP (DxP) cells was associated with a 2-fold higher basal ATPase activity relative to multidrug-resistant cell line MES-SA/Dx5 (Dx5) cells with wild-type P-gp. Cyclosporine inhibited ATPase activity in both cell types, whereas the cyclosporin D analog valspodar (PSC 833), vinblastine, and dactinomycin stimulated ATPase activity in Dx5 but not in mutant DxP cells. Moreover, the cell lines differed in their responses to verapamil, which produced greater stimulation of ATPase in Dx5 than DxP cells. Verapamil significantly reversed the [(3)H]daunorubicin accumulation defect in wild-type Dx5 cells, but it had no significant effect on [(3)H]daunorubicin accumulation in the mutant DxP cells. Verapamil was not transported by cells expressing either mutant or wild-type P-gp. Vanadate trapping of azido-ATP was markedly impaired in mutant P-gp. In conclusion, our data demonstrate that Phe(335) of transmembrane 6 is an important amino acid residue for the formation of cyclosporine and azidopine drug-binding site(s). Phe(335) also plays a role in the coupling of verapamil binding and modulation of daunorubicin intracellular accumulation in wild-type P-gp. In addition, Phe(335) in transmembrane 6 may play a role in coupling drug binding to ATPase activity. The deletion of Phe(335) results in a significant increase in the basal ATPase activity with a concomitant decrease in its ability to trap ATP and transport some P-gp substrates.

Interaction of anti-HIV protease inhibitors with the multidrug transporter P-glycoprotein (P-gp) in human cultured cells.

The anti-HIV protease inhibitors represent a new class of agents for treatment of HIV infection. Saquinavir, ritonavir, indinavir, and nelfinavir are the first drugs approved in this class and significantly reduce HIV RNA copy number with minimal adverse effects. They are all substrates of cytochrome P450 3A4, and are incompletely bioavailable. The drug transporting protein, P-glycoprotein (P-gp), which is highly expressed in the intestinal mucosa, could be responsible for the low oral bioavailability of these and other drugs which are substrates for this transporter. To determine whether these protease inhibitors are modulators of P-gp, we studied them in cell lines which do and do not express P-gp. Saquinavir, ritonavir and nelfinavir significantly inhibited the efflux of [3H]paclitaxel and [3H]vinblastine in P-gp-positive cells, resulting in an increase in intracellular accumulation of these drugs. However, similar concentrations of indinavir did not affect the accumulation of these anticancer agents. In photoaffinity labeling studies, saquinavir and ritonavir displaced [3H]azidopine, a substrate for P-gp, in a dose-dependent manner. These data suggest that saquinavir, ritonavir, and nelfinavir are inhibitors and possibly substrates of P-gp. Because saquinavir has a low bioavailability, its interaction with P-gp may be involved in limiting its absorption.

La relación de Helicobacter pylori con la displasia y el cáncer gástrico en Costa Rica / The association between Helicobacter pylori with displasia and gastric cancer in Costa Rica

Se comparó la incidencia de la bacteria Helicobacter pylori en un lugar de baja incidencia de cáncer gástrico, Poás (15.13 por ciento) y otro de incidencia muy alta, Puriscal (83.53 por ciento). Se eligió a 185 adultos de cada cantón, similares en edad y sexo y se practicó un estudio serológico para buscar anticuerpos IgG para H. pylori, y una gastroscopía para tomar dos biopsias por caso. Los resultados no apoyan la existencia de una fuerte relación entre H. pylori y cáncer gástrico

Ictericia obstructiva de origen neoplásico: una realidad lamentable / Obstructive jaundice of neoplastic origin: a sadness reality

El objetivo de este trabajo es analizar la ubicación del tumor primario y las posibilidades terapéuticas de la ictericia obstructiva secundaria a una lesión neoplásica de la vía biliar. Se estudió un total de 129 pacientes, portadores de una ictericia de origen maligno. La obstrucción se localizó en la vía biliar proximal en 109 (84,5 porciento) y en la región periampular en 19 (14,7 porciento). No fue definida en un caso (0,8 porciento). De los resultados de este trabajo se concluye que la principal causa de ictericia obstructiva maligna en Chile es el cáncer de vesícula biliar. Dentro de las neoplasias que originan ictericia, las periampulares ocupan un lugar secundario. Al momento del diagnóstico ningún paciente con un tumor de la via biliar proximal tiene posibilidades de curación y solo un 1/5 de los con tumores periampulares puede ser resecado con intenciones curativas